NK cells have been implicated in innate immunity against intracellular bacteria, parasites, viruses, and tumors. A delicate balance between activating and inhibitory receptors regulates the effector function of these cells. The inhibitory receptors are characterized by the presence of immunoreceptor tyrosine-based inhibitory motifs (ITIM) in their cytoplasmic domains that upon tyrosine phosphorylation recruit cellular phosphatases, e.g. SHP-1 or SHP-2, resulting in transient inactivation of the cells. The membrane receptors responsible for NK cell activation are less well characterized. However, many of these activating receptors are associated with DAP12, CD3zeta, or the FcERI-y adaptor proteins. These are type I membrane proteins, expressed as disulfide-bonded dimers, that contain immunoreceptor tyrosine-based motifs (ITAM) in the cytoplasmic domains. These proteins are considered adaptors, rather than receptors, because they contain very short extracellular domains that probably lack the ability to bind ligands. Rather, these signaling adaptors associate non-covalently with several different ligand-binding receptors, which themselves lack intrinsic signaling capacity. The goal of this project is to define the structure, ligand specificity, and function of the activating receptors expressed by NK cells. In particular, the specific aims are: 1) to define the functional relationship between the signaling adapter proteins DAPI2, CD3zeta, and FcERIy, and identify their associated receptors in NK cells, 2) to determine the role of DAP12, CD3zeta, and FceRI-y in NK cell development and function by the study of mice lacking these adaptor proteins, 3) to establish the biological role of the CD94/NKG2A and CD94/NKG2C receptors for Qaib by analysis of CD94-deficient mice and 4) to identify the ligand specificity of activating NK cell receptors in order to understand their significance in immune responses. These studies promise to provide new insights into the role of innate immunity in protection against pathogens and cancer.